A substantial body of research has developed concerning the role of serotonin (5-HT) in the etiology and treatment of major depressive disorder (MDD). The first section of this chapter summarizes the clinical evidence implicating alterations of the serotonergic system in the etiology of MDD. A general serotonin vulnerability has been proposed as a major risk factor in MDD, consisting of the composite risk factors from different components of 5-HT transmission. The effects of abnormal 5-HT synthesis, receptor function and genetic polymorphisms are discussed. The second section reviews some of the preclinical models and tests that are used to measure depressive behaviors and the efficacy of antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs). This section is focused on models that are commonly used in rodent species. Models and tests that require either acute or chronic antidepressant administration to achieve behavioral alterations are covered. The third section reviews the preclinical (rodent) literature concerning the role of individual 5-HT receptors in the development and pharmacological treatment of depressive behaviors. The effects of 5-HT depletion and of manipulation of the 5-HT transporter are also discussed. Although identifying the 5-HT receptors that support the therapeutic effects of SSRIs may lead to the development of more effective antidepressant drugs with fewer side effects, it is unclear whether the complete antidepressant effect of SSRIs can be reproduced by a single selective 5-HT receptor agonist or antagonist.